1. Field of the Invention
The present invention relates to novel antimycobacterial compounds or pharmaceutically acceptable derivatives thereof, and methods for making the same. More specifically, this invention relates to novel derivatives of phenyl 4-aminosalicylate or pharmaceutically acceptable derivatives thereof, and methods for making the same. The compounds and pharmaceutical compositions of this invention may be advantageously used as agents against mycobacterial infections.
2. Description of the Related Art
The designation of tuberculosis as a global public health crisis by the World Health Organization in the mid-1990""s has underscored the stern challenges facing the research community. The occurrence of some three million new cases of tuberculosis per year world-wide and the emergence of new strains of Mycobacterium tuberculosis characterized by drug resistance or increased virulence have made clear the pressing need for the evolution of newer and more powerful drugs. Moreover, several other mycobacterial diseases have begun to emerge, caused by nontuberculous mycobacteria. These include diseases caused by Mycobacterium avium, Mycobacterium ulcerans, Mycobacterium marinum, Mycobacterium kansasii and Mycobacterium haemophilum. 
It is has been known in the art that phenyl 4-aminosalicylate has value as an antituberculosis compound. Tests have suggested that phenyl 4-aminosalicylate destroys the virulent strain of M.tuberculosis (H37Rv) even better than 4-aminosalicylic acid, a standard widely-used antituberculosis drug to which it is structurally related. (U.S. Pat. No. 2,604,488 (to Soc. Usines Chim. Rhone-Poulenc); Chemical Abstracts, vol. 48, 12807 c (1954).) The present invention provides useful, novel antimycobacterial compounds, namely derivatives of phenyl 4-aminosalicylate, which are effective against a number of species of mycobacteria.
In addition to the need for the evolution of newer and more powerful antimycobacterial drugs, the biological evaluation of compounds suspected to be active against mycobacteria requires that the compounds be readily available in pure form on quantity scale, generally understood to be gram or multi-gram scale, as opposed to milligram scale. Gram scale quantities are necessary for the large numbers of biological tests which must be performed and replicated for the evaluation of a new drug candidate.
Products of synthetic reactions are most desirable when they can be easily and cheaply obtained as dry and free-flowing solids. In the long run, dry and free-flowing solids permit better formulations of drugs as tablets, capsules or syrups. The invention disclosed herein provides a novel method of phenyl 4-aminosalicylate derivative synthesis which yields products directly as dry free-flowing solids in analytically pure form. The products of the prior art syntheses are obtained as intractable oils which are difficult and labor-intensive to purify or bring into dry free-flowing form. The present invention overcomes these drawbacks and provides methods of phenyl 4-aminosalicylate derivative synthesis which yield products that are suitable for biological evaluation or for further chemical transformation to other derivatives of phenyl 4-aminosalicylate.
Broadly, the invention comprises novel derivatives of phenyl 4-aminosalicylate or pharmaceutically acceptable derivatives thereof, and methods for making the same. This invention further comprises methods for their preparation, to their use as therapeutic agents and to pharmaceutical compositions containing them. More particularly, this invention comprises methods of yielding novel derivatives of phenyl 4-aminosalicylate which have improved antimycobacterial activity and are comprised of structural elements which change the reaction chemistry and physical properties at the conjugation sites of phenyl 4-aminosalicylate during xenobiotic transformation. This invention further provides a method of yielding novel derivatives of phenyl 4-aminosalicylate having enhanced lipophilicity with respect to 4-aminosalicylic acid itself, signifying better permeation of the mycobacterial cell wall lipid domain and better drug action, on a multi-gram scale and in high purity for subsequent biological evaluation in drug discovery.
In one aspect, the invention comprises an antimycobacterial compound which comprises the formula: 
where R1=H; and
where R2-R3=CHR4 where R4=Cl to C14 alkyl, C1 to C14 substituted alkyl, C2 to C10 alkenyl, C2-C10 substituted alkenyl, C2 to C9 substituted dialkenyl, C3 to C7 cycloalkyl, C3 to C7 substituted cycloalkyl, phenyl, substituted phenyl, C7 to C16 phenylalkyl, C7 to C16 substituted phenylalkyl, benzyl, substituted benzyl, naphthyl, substituted naphthyl, heterocycle, or substituted heterocycle; or a pharmaceutically acceptable salt thereof; or a pharmaceutical isomer thereof; or a combination of the same.
Another aspect of the invention comprises an antimycobacterial compound which comprises the formula: 
where R1=H, COR5 where R5=C1 to C14 alkyl, C1 to C14 substituted alkyl, trifluoromethyl, trichloromethyl, dichloromethyl, chloromethyl, trideuteriomethyl, iodomethyl, C1 to C10 alkoxy, C1 to C10 substituted alkoxy, benzyloxy, substituted benzyloxy, steroidal, propenyloxy, difluorochloromethyl, pentafluoroethyl, perfluoropropyl, C2-C20 substituted alkenyloxy, C2 to C10 alkenyl, C2-C10 substituted alkenyl, C2 to C9 substituted dialkenyl, C3 to C7 cycloalkyl, C3 to C7 substituted cycloalkyl, phenyl, substituted phenyl, aminoalkyl, substituted aminoalkyl, C7 to C16 phenylalkyl, C7 to C16 substituted phenylalkyl, benzyl, substituted benzyl, naphthyl, substituted naphthyl, heterocycle, or substituted heterocycle;
where R2=H; and
where R3=COR6 where R6=C1 to C14 alkyl, C1 to C14 substituted alkyl, trifluoromethyl, trichloromethyl, dichloromethyl, chloromethyl, trideuteriomethyl, iodomethyl, C1 to C10 alkoxy, C1 to C10 substituted alkoxy, benzyloxy, substituted benzyloxy, steroidal, propenyloxy, difluorochloromethyl, pentafluoroethyl, perfluoropropyl, C2-C20 substituted alkenyloxy, C2 to C10 alkenyl, C2-C10 substituted alkenyl, C2 to C9 substituted dialkenyl, C3 to C7 cycloalkyl, C3 to C7 substituted cycloalkyl, phenyl, substituted phenyl, aminoalkyl, substituted aminoalkyl, C7 to C16 phenylalkyl, C7 to C16 substituted phenylalkyl, benzyl, substituted benzyl, naphthyl, substituted naphthyl, heterocycle, or substituted heterocycle;
or a pharmaceutically acceptable salt thereof; or a pharmaceutical isomer thereof; or a combination of the same.
Another aspect of the invention comprises an antimycobacterial compound of the formula: 
where R1=H, COCH3, COCH2CH3;
where R2=H; and
where R3=COCH3, COCH2CH3, CSNHC6H5, CSNH-4-C6H4Br, CSNH-4-C6H4CH3, CSNH-4-C6H4Cl, CSNHCH2CH3, CSNHCH(CH3)2, CSNHC(CH3)3, CSNH-3-pyridyl, CSNH-2,3,4-C6H2F3, CSNH-4-C6H4F, CSNH-3,5-C6H3F2, CSNH-2,6-C6H3F2, CSNH-2-Cl-4-NO2C6H3, CSNH-2-F-4-BrC6H3, CSNH-4-C6H4NO2, CSNH-3-CF3-4-Clxe2x80x94C6H3, CSNH-2-F-5-CF3-C6H3, CSNH-2-CF3-4-Fxe2x80x94C6H3, CSNH-3-CF3-4-Fxe2x80x94C6H3, CSNH-2-C6H4OCF3, CSNH-4-C6H4OCF3, CSNH-4-C6H4CF3, CSNH-2-C6H4SCF3, CSNH-3-C6H4CN, CSNH-4-C6H4CN, CSNH-2-C6H4OCHF2, CSNH-4-C6H4OCHF2, CSNH-4- C6H4OCH3, CSNH-3-C6H4CH3, CSNH-2-OCH3-4-NO2C6H4, CSNH-4-C6H4SCH3, CSNH-3,5-(CF3)2-C6H4, CSNH-3,4,5-(CH3)3C6H2, CSNH-1-naphthyl and CSNH-2-naphthyl; or a pharmaceutically acceptable salt thereof; or a pharmaceutical isomer thereof; or a combination of the same.
Another embodiment of the invention comprises an antimycobacterial compound of the formula: 
where R1=H, COCH3, COCH2CH3; and
where R2=H; and
where R3=COCH3, COCH2CH3, CSNHC6H5, CSNH-4-C6H4Br, CSNH-4-C6H4CH3, CSNH-4-C6H4Cl; or a pharmaceutically acceptable salt thereof; or a pharmaceutical isomer thereof; or a combination of the same.
Another aspect of the invention comprises the formula X wherein R1=H, R2=H, and R3=CSNHC6H5, CSNH-4-C6H4Br, CSNH-4-C6H4CH3 and CSNH-4-C6H4Cl.
In yet another aspect, the invention comprises the formula X wherein R1=H, and R2-R3=CH-2-C6H4NO2, CH-4-C6H4NO2 and CH-4-C6H4CHO.
Yet another aspect of the invention comprises a compound of the formula: 
wherein the compound exhibits enhanced and unexpected activity against mycobacteria selected from the group consisting of M.tuberculosis. 
Another aspect of the invention comprises a compound of the formula: 
wherein the compound exhibits enhanced and unexpected activity against mycobacteria selected from the group consisting of M.tuberculosis. 
In yet another aspect, the invention comprises the formula: 
wherein the compound exhibits enhanced and unexpected activity against mycobacteria selected from the group consisting of M.tuberculosis. 
Another aspect of the invention comprises a compound of the formula: 
wherein the compound exhibits enhanced and unexpected activity against mycobacteria selected from the group consisting of M.tuberculosis. 
In yet another aspect, the invention comprises a compound of the formula: 
wherein the compound exhibits enhanced and unexpected activity against mycobacteria selected from the group consisting of M.tuberculosis. 
Suitable pharmaceutically-acceptable salts include acid addition salts such as methanesulfonate, fumarate, hydrochloride, hydrobromide, citrate, maleate and salts formed with phosphoric and sulfuric acid. In another aspect suitable salts are base salts such as an alkali metal salt, for example sodium, an alkaline earth metal salt, for example calcium or magnesium, an organic amine salt, for example triethylamine, morpholine, N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine or amino acids, for example lysine. There may be more than one cation or anion depending on the number of charged functions and the valency of the cations or anions. A preferred pharmaceutically-acceptable salt is the sodium salt.
It is to be understood that certain compounds of formula X can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is also to be understood that the invention encompasses all such solvated forms which possess antimycobacterial activity.
It is also to be understood that the invention relates to all tautomeric forms of compound of formula X that possess antimycobacterial activity. More particularly, it is to be understood that the invention encompasses all optical, diastereo- and regio-isomers of formula X that possess antimycobacterial activity.
The invention also broadly comprises the syntheses of the novel derivatives of phenyl 4-aminosalicylate. Further, the invention comprises the syntheses of novel derivatives of phenyl 4-aminosalicylate on multi-gram scale and in high purity for subsequent biological evaluation in drug discovery.
Another aspect of the invention comprises a method for synthesizing an antimycobacterial compound of the formula: 
where R=C1 to C14 alkyl, C1 to C14 substituted alkyl, C2 to C10 alkenyl, C2-C10 substituted alkenyl, C2 to C9 substituted dialkenyl, C3 to C7 cycloalkyl, C3 to C7 substituted cycloalkyl, phenyl, substituted phenyl, C7 to C16 phenylalkyl, C7 to C16 substituted phenylalkyl, benzyl, substituted benzyl, naphthyl, substituted naphthyl, heterocycle, or substituted heterocycle,
which comprises adding para-aminosalicylic acid phenyl ester with a reactive aldehyde comprised of the formula:
RCHO
where R=C1 to C14 alkyl, C1 to C14 substituted alkyl, C2 to C10 alkenyl, C2-C10 substituted alkenyl, C2 to C9 substituted dialkenyl, C3 to C7 cycloalkyl, C3 to C7 substituted cycloalkyl, phenyl, substituted phenyl, C7 to C16 phenylalkyl, C7 to C16 substituted phenylalkyl, benzyl, substituted benzyl, naphthyl, substituted naphthyl, heterocycle, or substituted heterocycle,
to form a reaction mixture. The reaction mixture is characterized in that the mole ratio of para-aminosalicylic acid phenyl ester to reactive aldehyde is about 0.93 to 1.00. The reaction mixture is refluxed and evaporated to form XI. The molar ratio is critical to the production of compound XI in a dry, free flowing solid form.
In yet another aspect, the invention comprises a method for synthesizing an antimycobacterial compound of the formula: 
where R=C1 to C14 alkyl, C1 to C14 substituted alkyl, C2 to C10 alkenyl, C2 to C10 substituted alkenyl, C2 to C9 substituted dialkenyl, C3 to C7 cycloalkyl, C3 to C7 substituted cycloalkyl, phenyl, substituted phenyl, C7 to C16 phenylalkyl, C7 to C16 substituted phenylalkyl, benzyl, substituted benzyl, naphthyl, substituted naphthyl, heterocycle, or substituted heterocycle,
which comprises adding para-aminosalicylic acid phenyl ester with a mustard oil comprised of the formula:
RNCS
where R=C1 to C14 alkyl, C1 to C14 substituted alkyl, C2 to C10 alkenyl, C2-C10 substituted alkenyl, C2 to C9 substituted dialkenyl, C3 to C7 cycloalkyl, C3 to C7 substituted cycloalkyl, phenyl, substituted phenyl, C7 to C16 phenylalkyl, C7 to C16 substituted phenylalkyl, benzyl, substituted benzyl, naphthyl, substituted naphthyl, heterocycle, or substituted heterocycle,
to form a reaction mixture. The reaction mixture is characterized in that the mole ratio of para-aminosalicylic acid phenyl ester to mustard oil is about 0.95 to 1.00. The reaction mixture is refluxed and cooled to produce XII. The molar ratio is critical to the production of compound XII in a dry, free flowing solid form.
Another aspect of the invention comprises a method for synthesizing an antimycobacterial compound of the formula: 
where R=C1 to C14 alkyl, C1 to C14 substituted alkyl, trifluoromethyl, trichloromethyl, dichloromethyl, chloromethyl, trideuteriomethyl, iodomethyl, C1 to C10 alkoxy, C1 to C10 substituted alkoxy, benzyloxy, substituted benzyloxy, steroidal, propenyloxy, difluorochloromethyl, pentafluoroethyl, perfluoropropyl, C2-C20 substituted alkenyloxy, C2 to C10 alkenyl, C2-C10 substituted alkenyl, C2 to C9 substituted dialkenyl, C3 to C7 cycloalkyl, C3 to C7 substituted cycloalkyl, phenyl, substituted phenyl, aminoalkyl, substituted aminoalkyl, C7 to C16 phenylalkyl, C7 to C16 substituted phenylalkyl, benzyl, substituted benzyl, naphthyl, substituted naphthyl, heterocycle, or substituted heterocycle,
which comprises adding para-aminosalicylic acid phenyl ester with a carboxylic acid anhydride comprised of the formula:
(RCO)2O
where R=C1 to C14 alkyl, C1 to C14 substituted alkyl, trifluoromethyl, trichloromethyl, dichloromethyl, chloromethyl, trideuteriomethyl, iodomethyl, C1 to C10 alkoxy, C1 to C10 substituted alkoxy, benzyloxy, substituted benzyloxy, steroidal, propenyloxy, difluorochloromethyl, pentafluoroethyl, perfluoropropyl, C2-C20 substituted alkenyloxy, C2 to C10 alkenyl, C2-C10 substituted alkenyl, C2 to C9 substituted dialkenyl, C3 to C7 cycloalkyl, C3 to C7 substituted cycloalkyl, phenyl, substituted phenyl, aminoalkyl, substituted aminoalkyl, C7 to C16 phenylalkyl, C7 to C16 substituted phenylalkyl, benzyl, substituted benzyl, naphthyl, substituted naphthyl, heterocycle, or substituted heterocycle,
or with its synthetic equivalent, such as a mixed anhydride of the formula:
CF3SO3COCF3
to form a reaction mixture. The reaction mixture is characterized in that the mole ratio of para-aminosalicylic acid phenyl ester to carboxylic acid anhydride is about 0.06 to 1.00. The reaction mixture is refluxed, cooled and dried to produce compound XIII. The molar ratio is critical to the production of compound XIII in a dry, free flowing solid form.
Another aspect of the invention comprises a method for synthesizing a compound comprised of the formula: 
which comprises adding para-aminosalicylic acid phenyl ester with para-terephthalaldehyde in absolute ethanol to form a reaction mixture, boiling the reaction mixture, refluxing the reaction mixture, distilling the reaction mixture and filtering the reaction mixture to yield compound I.
In yet another aspect, the invention comprises a method for synthesizing a compound comprised of the structure: 
which comprises adding para-aminosalicylic acid ester to absolute ethanol to form a reaction mixture, refluxing the reaction mixture, adding phenyl isothiocyanate to the reaction mixture to form a second reaction mixture, refluxing the second reaction mixture and cooling the second reaction mixture to yield II.
Another aspect of the invention comprises a method for synthesizing a compound comprised of the structure: 
which comprises adding para-aminosalicylic acid phenyl ester to para-nitrobenzaldehyde and ethanol to form a reaction mixture, refluxing the reaction mixture, distilling the reaction mixture, evaporating the reaction mixture to form a precipitate and washing and drying the precipitate to yield compound III.
In yet another aspect, the invention comprises a method for the synthesis of a compound comprised of the structure: 
which comprises adding para-aminosalicylic acid phenyl ester to ortho-nitrobenzaldehyde and ethanol to form a reaction mixture, refluxing the reaction mixture, distilling the reaction mixture, evaporating the reaction mixture to form a precipitate and washing the precipitate and filtering the precipitate to yield compound IV.
Another aspect of the invention comprises a method for the synthesis of a compound comprised of the structure: 
which comprises adding para-aminosalicylic acid phenyl ester to acetic anhydride to form a reaction mixture, boiling and refluxing the reaction mixture, cooling the reaction mixture and drying the reaction mixture to yield compound V.
The pharmaceutical compositions of this invention may be prepared by combining the compound X of this invention with a solid or liquid pharmaceutically acceptable carrier, and optionally, with pharmaceutically acceptable adjuvants and excipients employing standard and conventional techniques. Solid form compositions include powders, tablets, dispersible granules, capsules and suppositories. A solid carrier can be at least one substance which may also function as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, tablet disintegrating agent, and encapsulating agent. Inert solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, cellulosic materials, low melting wax, cocoa butter, and the like. Liquid form compositions include solutions, suspensions and emulsions. For example, there may be provided solutions of the compounds of this invention dissolved in water, water-propylene glycol, and water-polyethylene glycol systems, optionally containing conventional coloring agents, flavoring agents, stabilizers and thickening agents.
The pharmaceutical composition can be provided by employing conventional techniques. Preferably the composition is in unit dosage form containing an effective amount of the active component, that is, the compound of formula X according to this invention.
The invention will be described with reference to following non-limiting examples.

The para-aminosalicylic acid phenyl ester Schiff bases were prepared by the reactions of para-aminosalicylic acid phenyl ester with reactive aldehydes. The reaction conditions, which included reactions times, work-up methods, and methods for inducing crystallization, were critical and insured that the products of the syntheses were obtained in acceptable yield and purity.
para-Aminosalicylic acid phenyl ester and the appropriate reactive aldehyde were weighed into a round bottom flask. The volume of the flask was chosen in such a way that the contents of the entire reaction mixture did not exceed 50% of the flask""s nominal capacity. The flask was fitted for reflux with a magnetic stirrer, temperature controlled heating mantle and reflux condenser. Sufficient absolute ethanol was added to make the resulting reaction mixture solution 0.13 Molar in para-aminosalicylic acid phenyl ester and 0.14 Molar in the reactive aldehyde. This characteristically made the mole ratio of para-aminosalicylic acid phenyl ester to reactive aldehyde to be about 0.93 to 1.00. The mixture was brought to the boiling point, and refluxing was continued for three hours. This amount of reflux time was necessary for complete conversion. During the three hours of refluxing, the reaction mixture can change color and can vary in color from light yellow to dark yellow, depending on the specific reactive aldehyde.
After three hours, half of the ethanol is distilled away, using a Dean-Stark trap as distillation apparatus. The solvent can be recovered and recycled for use in future procedures. The concentrated reaction mixture is turned out into a crystallizing dish and allowed to evaporate to form a solid. The solid is washed with several portions of ether, such that the total volume of ether is half of the volume of absolute ethanol used for the original reaction mixture. The infrared spectrum of this material showed the expected bands for the formation of the Schiff base, viz., infrared bands at ca. 3100, 1675 and 1300 cmxe2x88x921, diagnostic for the completion of the desired reaction.
The material was taken up in just the minimum volume of ethyl acetate required. After stirring for several minutes, petroleum ether (bp 30-60xc2x0 C.) was added with care to the ethyl acetate solution in an amount of about ten times the volume of ethyl acetate that had been required thereby producing a cloudy mixture. The obtained mixture was allowed to stand over night, producing a well-defined solid material. The material was gravity filtered through Whatman No. 1 filter paper and dried on a porous porcelain plate to yield the Schiff base as a dry free-flowing solid. The tan to yellow solid obtained was analyzed by usual means, including the determination of physical constants, infrared and magnetic resonance spectroscopy and elemental analysis.

The para-aminosalicylic acid phenyl ester thioureides were prepared by the reactions of para-aminosalicylic acid phenyl ester with reactive mustard oils. The reaction conditions, which included reaction times, work-up methods, and methods for inducing crystallization, were critical and insured that the products of the syntheses were obtained in acceptable yield and purity.
para-Aminosalicylic acid phenyl ester was weighed into a round bottom flask. The volume of the flask was chosen in such a way that the contents of the entire reaction mixture did not exceed 50% of the flask""s nominal capacity. The flask is fitted for reflux with a magnetic stirrer, temperature controlled heating mantle and reflux condenser. Sufficient absolute ethanol was added to make the resulting reaction mixture solution 0.3 Molar in para-aminosalicylic acid phenyl ester. The mixture was brought to reflux, producing a clear homogeneous solution. To this solution at the boil was added the appropriate mustard oil as a 0.17 Molar solution in absolute ethanol, at such a rate that vigorous reflux was maintained. The mustard oil was then washed in with a further portion of ethanol, equivalent in volume to the amount used to prepare the mustard oil solution. This characteristically made the mole ratio of para-aminosalicylic acid phenyl ester to mustard oil to be about 0.95 to 1.00. Thus there must be only a slight excess of the reactive mustard oil. Too much of the mustard oil leads to impure product. The mixture was maintained at the boiling point, and refluxing was continued for one hour. This amount of reflux time was necessary to ensure complete conversion. During the hour of refluxing, the reaction mixture can change color and can vary in color from light yellow to dark yellow, depending on the reactive mustard oil used.
After an hour, half of the ethanol was removed. This can be accomplished by boiling the ethanol off, using a simple hot plate, or the ethanol can be distilled away, using a Dean-Stark trap as distillation apparatus. The solvent can be recovered and recycled for use in future procedures. The concentrated reaction mixture was allowed to stand to cool over several hours thereby depositing a white solid, which was removed from the mother liquor by careful decantation. In a crystallizing dish, the solid was washed with two portions of ether, such that the total volume of ether was 40% of the volume of absolute ethanol used for the original reaction mixture. The solid was allowed to dry and was present as a dry free-flowing solid. The white solid obtained was analyzed by the usual means, including the determination of physical constants, infrared and magnetic resonance spectroscopy and elemental analysis.

The para-aminosalicylic acid phenyl ester diacyl derivatives were prepared by the reactions of para-aminosalicylic acid phenyl ester with carboxylic acid anhydrides. Reaction conditions, which included reaction times, work-up methods, and methods for inducing crystallization, were critical and insured that the products of the syntheses are obtained in acceptable yield and purity.
para-Aminosalicylic acid phenyl ester was weighed into a round bottom flask. The volume of the flask was chosen in such a way that the contents of the entire reaction mixture did not exceed 50% of the flask""s nominal capacity. The flask was fitted for reflux with a magnetic stirrer, temperature controlled heating mantle and reflux condenser.
Sufficient carboxylic acid anhydride, such as acetic anhydride, was added to make the resulting reaction mixture a 0.63 Molar solution of para-aminosalicylic acid phenyl ester in anhydride. This characteristically makes the mole ratio of para-aminosalicylic acid phenyl ester to anhydride to be about 0.06 to 1.00. The mixture was gradually brought to the boiling point over 10 minutes, and refluxed for twenty minutes.
The mixture was allowed to cool to room temperature and to stand for two hours, then poured out onto a watch glass and allowed to dry. The resulting solid residue was ground with an amount of ether equivalent in volume to the volume of anhydride used in the original reaction. The ether was drawn off, and the process was repeated. The solid was allowed to dry to yield the diacyl derivative as a dry free-flowing solid. The white solid obtained was analyzed by usual means, including the determination of physical constants, infrared and magnetic resonance spectroscopy and elemental analysis.